Newly identified and potentially targetable mechanisms of immune cytopenias in PIDs. In this issue of Blood, Stepensky et al characterize the immune phenotype underlying a novel PID with early-onset Evans syndrome due to loss of a central cytoplasmic peptidase, TPPII.¹  Stepensky et al show that a stress-induced immunosenescence program is induced in T and B lymphocytes of human subjects with TPPII deficiency. This is also observed in other cell types, including fibroblasts, as well as in TPPII-deficient mice.¹  Together with a reduction of the antigen receptor diversity, loss of naive lymphocytes, reduced lymphocyte proliferative capacity, and deregulated apoptosis, this leads to an accumulation of autoreactive cells causing autoimmunity that largely resembles other newly described PIDs with cytopenia, such as LRBA deficiency, CTLA4 deficiency, PI(3)K hyperactivity, and loss of STK4,^4-7  as indicated. Of note, an immunosenescence-like abnormal differentiation of T cells has also been identified recently in one of the examples par excellence of autoimmune cytopenias, namely, ALPS-Fas.⁸  Many of these newly defined pathomechanisms of autoimmunity in PIDs will enable the use of existing drugs or the development of new targeted drugs. This may include complementation of CTLA4 deficiency for immune regulation, interfering with the Akt/mTOR pathway, or pharmacologically influencing the transcriptional programs and cytokine networks (eg, interleukin-6) behind the TH17-T_reg balance (as in the case of lost peripheral regulatory T cells due to STAT3 gain of function).⁹